Study of novel Ras signaling pathway using ras knockout mice

Principal Investigator

AIBA Atsu The University of Tokyo, The Institute of Medical Science, Associate Professor, 医科学研究所, 助教授 (20271116)

Co-Investigator(Kenkyū-buntansha)

NAKAO Kazuki The University of Tokyo, The Institute of Medical Science, Visiting Research Associate, 医科学研究所, 寄付研究部門教員 (20217657)
NAKAMURA Kenji The University of Tokyo, The Institute of Medical Science, Research Associate, 医科学研究所, 助手 (90253533)

We generated H-ras, N-ras and K-ras deficient mice and multiple ras mutant mice, and found that H-ras and N-ras mutant mice as well as H-ras N-ras double mutant mice apparently developed normally, but K-ras mutant mice were embryonic lethal. We introduced human H-ras transgene into a single and multiple ras mutant mice and found that H-ras transgene rescue all abnormality exhibited in the development of these ras mutant mice, suggesting that the function of ras genes is redundant in embryonic and neonatal development.We showed that H-ras null mutant mice develop approximately seven times less papillomas compared with wild-type littermates do after 20 weeks of TPA treatment. 13 (62%) out of 21 papillomas in H-ras null mutant mice have activated mutations of K-ras gene. This suggests that activation of K-ras gene can replace the H-ras activation in the initiation step of skin tumor development.In the H-ras null mutant hippocampus, the tyrosine phosphorylation of NR2A (ε1) and NR2B (ε2) subunits of NMDA receptors is increased and correspondingly NMDA synaptic responses are selectively enhanced. In addition, long-term potentiation (LTP) is markedly enhanced in mutant mice most likely due to a selective enhancement of NMDA synaptic responses. Therefore, although Ras proteins have been implicated in cell proliferation and differentiation, the regulation of activity-dependent synaptic plasticity in the adult animals by downregulation of the phosphorylation of the NMDA receptor may be another major and pivotal role for H-Ras protein. To investigate the relationship between Ras signaling pathway and NMDA receptor, we stimulate hippocampal culture cell by NMDA.We found that dephosphorylation of NMDA receptor occured as well as activation of ERK and p38 MAPK.We found that the activation of ERK by NMDA stimulation requires Ras activity.